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Electropharmacological Characterization of Aciclovir in the Halothane-Anesthetized Dogs: A Proposal of Evaluation Method for Cardiovascular Safety Pharmacology of Anti-virus Drugs

Cardiovascular Toxicology
Yoshiki Kondo, Mihoko Hagiwara-Nagasawa, Ryuichi Kambayashi, Ai Goto, Koki Chiba, Yoshio Nunoi, Hiroko Izumi-Nakaseko, Akio Matsumoto, Atsushi Sugiyama
Wichtige Hinweise
Handling Editor: Y. James Kang.

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Given limited information regarding the pathophysiology underlying aciclovir-associated, clinically observed cardiovascular adverse events including chest pain, tachycardia, bradycardia, palpitation, arrhythmia, hypertension and hypotension, we investigated its electropharmacological effects using the halothane-anesthetized beagle dogs. Aciclovir in doses of 2 and 20 mg/kg was sequentially infused over 10 min with an interval of 20 min (n = 4), which would achieve sub-therapeutic to supra-therapeutic levels of plasma concentrations. Aciclovir decreased the total peripheral vascular resistance along with the blood pressure in a dose-related manner, which increased the heart rate, ventricular contraction and atrioventricular nodal conduction speed probably via a reflex-mediated increase of sympathetic tone. No significant change was detected in the intra-atrial or intra-ventricular conduction, indicating that aciclovir may not inhibit atrial or ventricular INa. Aciclovir prolonged the repolarization period in a dose-related as well as in a reverse frequency-dependent manners, indicating that aciclovir may inhibit IKr, which was supported by the Tpeak − Tend prolongation. Aciclovir transiently prolonged the J − Tpeakc possibly through a reflex-mediated increase of sympathetic tone, indicating an increase of net inward current in the early repolarization phase. Thus, aciclovir may directly inhibit IKr, and also have the potential to indirectly induce Ca2+ overload leading to early afterdepolarization. These in vivo electropharmacological profile of aciclovir would partly explain the onset mechanism of clinical adverse events.

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